Direct Conversion of Human Fibroblasts into Neuronal Cells by Small Molecules (hCiN)

通过小分子 (hCiN) 将人成纤维细胞直接转化为神经元细胞

基本信息

批准号：
9254639
负责人：
Babak Esmaeli-Azad
金额：
$ 22.4万
依托单位：
CIBOTS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-15 至 2020-02-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9254639
关键词：
Alzheimer&apos s Disease Biological Assay Biotechnology Brain Brain Diseases Bypass Cell Count Cell Nucleus Cell Therapy Cells Cellular Assay Chemicals Child Abuse Chronic Crime Development Disease model Drug abuse Electrophysiology (science)Employment Engraftment Family Fibroblasts Future Generations Glutamates Goals Health Healthcare Systems Human In Vitro Lead Legal patent Methodology Modeling Molecular Mus Neurodegenerative Disorders Neurons Patients Pharmaceutical Preparations Phase Preclinical Drug Evaluation Prevention Research Societies Somatic Cell Spinal cord injury System Technology Testing Therapeutic Time Transplantation addiction base cholinergic cost drug discovery human embryonic stem cell illicit drug use in vitro Assay in vivo induced pluripotent stem cell innovation insight migration nerve stem cell nervous system disorder novel novel therapeutics personalized medicine small molecule tool

项目摘要

Licit and illicit drug use places a large burden on the nation's health care systems and the economy, costing more than $500 billion annually. Addiction is a chronic brain disease that leads to a compulsive desire for drugs despite significantly harmful consequences, including direct effects on health as well as detriments to society, including disintegration of families, child abuse, loss of employment, and a broad array of crimes. Reprogramming of human somatic cells to alter cellular identity has enormous potential for neurological disease modeling, high-throughput drug screening, cell therapy, and personalized medicine. However, several challenges remain before patient-specific cells produced by reprogramming can provide reliable insights into neurological disease mechanisms (e.g., Drug abuse/ addiction, other neurological disorders) or be efficiently applied to drug discovery and transplantation therapy. Using our innovative patented technology to develop Artificial 3D Microenvironment Niche and screen for reprogramming small molecules (US Patent # 9045737), we have developed a preliminary small molecule cocktail that efficiently (up to 50% of starting cell numbers, mostly Glutamatergic Neurons) and directly converts human fibroblasts into neurons, bypassing the neural progenitor stage (Chemically induced Neurons, hCiN). In this Phase I proposal, we attempt to demonstrate the feasibility of this methodology by optimizing our preliminary hCiN cocktails while investigating hCiN functionally with molecular, cellular, electrophysiological assays and in a mouse brain transplantation model.

合法和非法药物的使用给国家的医疗保健系统带来了沉重的负担经济，每年花费超过 5000 亿美元。成瘾是一种慢性大脑尽管有害但仍导致对药物的强迫性渴望的疾病后果，包括对健康的直接影响以及对社会的损害，包括家庭解体、虐待儿童、失业以及一系列广泛的问题的犯罪行为。对人类体细胞进行重新编程以改变细胞身份具有巨大的意义神经疾病建模、高通量药物筛选、细胞治疗的潜力，和个性化医疗。然而，在针对特定患者进行治疗之前，仍然存在一些挑战重编程产生的细胞可以为神经系统疾病提供可靠的见解机制（例如药物滥用/成瘾、其他神经系统疾病）或有效应用于药物发现和移植治疗。使用我们的创新专利开发人工 3D 微环境利基和筛选的技术重新编程小分子（美国专利# 9045737），我们开发了一种初步的小分子混合物，有效（高达起始细胞数量的 50%，主要是谷氨酸能神经元）并直接将人类成纤维细胞转化为神经元，绕过神经祖细胞阶段（化学诱导神经元，hCiN）。在这个第一阶段提案，我们尝试通过以下方式证明该方法的可行性优化我们的初步 hCiN 鸡尾酒，同时研究 hCiN 功能分子、细胞、电生理学测定以及小鼠脑移植模型。